PROJECT SUMMARY Intellectual Merit: Human babesiosis is a rapidly emerging tick-borne zoonosis in the United States caused by the protozoan Babesia microti and transmitted by Ixodes scapularis, the Lyme disease vector. Unlike Lyme disease, babesiosis is a potentially fatal disease and poses a threat to blood transfusion recipients. In the Northeast, both Lyme disease and babesiosis were originally restricted to coastal New England. While Lyme disease has expanded dramatically over the past thirty years and now is endemic from Maine to Virginia, babesiosis cases appears to be expanding at a slower rate for reasons that are not understood. This differential spread provides a unique opportunity to examine factors driving pathogen emergence by comparing these species' natural history and transmission dynamics. Furthermore, because B. microti encounters a large proportion of host populations already infected with 6. /jurgdor/er/throughout its geographic expansion, the goal ofthis study is to investigate how pathogen interactions at the individual, population, and community levels influence B. microti invasion patterns and enzootic prevalence. Evidence for a mutualistic effect of B. burgdorferi infection on B. m/crof/transmission are based on recent findings by .Diuk- Wasser and collaborators that coinfected hosts produce more S. m/crof/-infected ticks than 6. /77/crof/-only infected hosts in laboratory studies and that tick infection prevalence and human disease can be as high for 6. microti than B. burgdorferi at long-established sites. This project will directly compare transmission rates of both B. microti and B. burgdorferi in the laboratory by employing established colonies of /. scapularis and white-footed mice {Peromyscus leucopus) and will explore how host coinfection with both pathogens enhances B. m/crof/transmission (Aim 1). Scaling up from this system, Ro will be estimated for populations of infected and non-infected hosts to determine the extent to which coinfection drives invasion of B. microti into previously uninfected areas (Aim 2). A dynamic multi-host, multi-pathogen model will be developed to identify key factors determining B. microti infection prevalence in host-seeking nymphs once B. microti has become established (Aim 3). The proposed project is innovative because it investigates the drivers of an active invasion process for an emerging human pathogen; uses a comparative approach to identify key determinants ofthe invasion and persistence of two /. scapularls-borne pathogens; and examines the role of mutualistic interactions among vector-borne pathogens in invasion and persistence. Expected outcomes include elucidation ofthe mechanisms determining human exposure risk to a rapidly emerging, potentially lethal tick-borne pathogen, and the development of a transmission model including the effect of pathogen interactions. A long-term goal of this study is to develop optimal prevention and control strategies that can synergistically target 6. microti and 6. burgdorferi, as well as other known, or new, tick-borne pathogens. Broader Impacts: This project will employ one postdoctoral researcher, one PhD student researcher and three field assistants, as well as two high-school students from the Yale University Peabody Museum of Natural History Evolutions school program through an after school program for underserved populations with a demonstrated interest in the natural and environmental sciences. Yale undergraduate and Master's of Public Health students will be exposed to the findings ofthe research through Dr. Diuk-Wasser's Eco-Epidemiology course and will be encouraged to pursue undergraduate/MPH theses on different aspects of the project, providing a unique opportunity for bridging ecological and epidemiological concepts. This project will make an important and novel contribution to public health by elucidating the ecological mechanisms of spread and persistence of the human babesiosis and Lyme disease agents. The results from our studies will be disseminated among a wide variety of scientific journals, and will be presented at scientific meetings that target ecologists, evolutionary biologists, mathematical modelers, and public health scientists. The results will also be disseminated widely to popular media outlets through press releases and interviews upon the publication of important findings, as well as through independent organizations, such as the American Lyme Disease Foundation and through the Lyme disease iPhone App. This project will make an important and novel contribution to public health by elucidating ecological mechanisms of persistence and spread of the agents of human babesiosis and Lyme disease. It will help increase public and physician's awareness ofthe emerging risk of babesiosis and the probability of coinfection causing more serious symptoms than either disease alone. Development of a study design and modeling framework for the study of interactions among multiple pathogens will also inform studies of a range of pathogens typically studied in isolation.